The main goal of the current proposal is to identify the molecular and neurobehavioral abnormalities in young adulthood resulting from the genetic mutations of the microtubule-related genes associated with schizophrenia (SZ), such as PCM1, DPYSL2, and 16p11 copy number variations (CNVs), and how these alterations can be exacerbated by adolescent social isolation to produce a full-blown psychiatric disorder in young adulthood. We hypothesize that mice with the microtubule-associated genetic mutations will display stress-related molecular alterations and abnormal prefrontal cortex (PFC) maturation during adolescence and/or young adulthood, leading to adult behavioral phenotypes resembling different dimensions of SZ. Aim 1 will identify the genetic mutations-produced neurobehavioral abnormalities that can be exacerbated by adolescent social isolation in mice. We will identify the effects of the genetic risk factors on SZ-related behaviors as well as maturation of GABAergic interneurons and dendritic spines of pyramidal neurons in the PFC. We will also examine if these phenotypes are exacerbated by adolescent social isolation. Aim 2 will determine the genetic mutations- produced molecular changes that can be intensified by adolescent social isolation. Specifically, we will evaluate expression of the candidate stress-related factors and the global transcriptome changes in PFC. Aim 3 will identify alterations in stress-associated molecules in peripheral blood samples collected from two independent prospective cohorts and compare the human results with those from the mouse models. The project will determine alteration in stress-related molecular expression induced by genetic mutations, leading to impaired PFC maturation during adolescence and adult behavioral consequences, which may underlie susceptibility to detrimental effects of adolescent social isolation. Our project will facilitate future development of prognostic measures and biomarkers to help identify prodromal signs of the disease.